Opioids II Flashcards
What are the patterns of use of opioids?
- many users are chippers –> occasional use (this proves that people do not become instantly addicted)
- there are also “needle freaks” which are people who associate IV injection with the drug and start to enjoy the act of the injection almost more than the drug itself and can do harmful things like start injecting themselves with any fluid to get high
- true addicts use min. once daily to 20 or more times a day
can be expensive up to $600 a day or more which is why people resort to crime when they have these addictions
only 10-15% of people who try opioids will have potential for long term addiction
What are the four distinct families of endogenous opioid-like substances and their receptors? And what are their functions?
- enkephalins (delta)
- endorphins (mu)
- endorphins (mu)
- dynorphins (kappa)
each family is derived from different precursor proteins
- all contain tyrosine at their N-terminus
- parts of the morphine mimic the tyrosine which is an amino group separated from a phenyl ring by two carbons
- it may function as NT, neurohormones or neuromodulators
- involved in pain, placebo response, acute stress responses and social attachment
What are the different (3) types of opioid receptors?
mu: euphoria, respiratory depression, analgesia, dependence. –> has a large open binding pocket that may allow for rapid exchange of ligands
delta: some analgesic effects
kappa: dysphoria, negative effects, some analegsic effects
for the mu receptor: the binding site is buried in the middle with the opiod attached to it. Usually receptor pockets close when bound to agnostic but in Mu receptor case, it doesn’t and its wide open, so when you give an antidote, it has a rapid effect because it has access to the binding pocket and can compete with the agnoist
What happens to neurotransmitter release when opiod receptors are activated?
they inhibit all adenyl cyclase and reduce cAMP levels
opioids tend to decrease neuronal excitability at the cellularr level which is why they are so good at interrupting pain signals
in the reward pathway, they increase dopamine release in the NA by inhibiting inhibition
What happens presynaptically when opioids bind to their receptors?
inhibit nT release by inhibiting calcium influx via inhibition of the opening of mostly N-type voltage gated calcium channels
What happens postynaptically when opioids bind to their receptors?
hyperpolarizsation of the membrane by enhancing K+ flow outwards by stimulating the opening of specific potassium channels
How does the VTA to NA pathway works without presence of opioids?
in the absence of opioids, GABA is released from one presynaptic terminal
it binds to GABA-A receptor on different presynaptic terminal
this has an inhibitory effect NT (dopamine release)
How does the VTA to NA pathway works in the presence of opioids?
when opipods are present they bind to presynaptic receptors which has an inhibitory effect on GABA release
therefore less GAAB binds to the GABA-A receptor on the adjacent nerve ending
net result is that more dopamine is released
more activation of postsynaptic dopamine receptors
What is the relationship between opioids and dopamine release?
small changes in dopamine levels in the NA in animals which shows less addictive properties??
morphine produces the same change in dopamine levels as nicotine
heroin users have claimed that quitting cigarettes was as difficult or even more so
Nutt’s paper proposes that dopamine is only important for the craving of opioids but not for the reward or euphoria
How does tolerance develop in opioid users?
develops to analgesia, vomitting, euphoria, and respiratory. depression
constipation and pupil constriction affected very little
addicts can take as much as 50 times the normal analgesic dose of morphine with little respiratory depression which can lead to problems if they stop using for a period of time, lose tolerance and then resume with same dose (i.e. rehab can cause OD’s)
What are the mechanisms of tolerance?
some mu receptors internalize to acute use
loss of effect of activated receptor on cAMP levels –> activated receptors no longer inhibits adenyl cyclase
long term receptor down regulation but not always shown to be part of tolerance
up regulation of the neurotransmitter receptors and effects on neurogenesis and neuronal structure
What kind of damage can heroine cause?
many studies have found no major damage to organs of heroin users
most damage is due to poor nutrition, adulterated (impure drugs), infections from needles (hepatitis, HIV), concomitant drug use and general lifestlye
analgesic effects mask pain of infections or problems
What happens in the case of a overdose (3 things)?
Opioid overdose “triad”:
- coma
- depressed respiration
- pinpoint pupils
death from respiratory depression
What can cause overdose in opioid addicts?
- can happen when thees a new supplier, and heroin goes from being impure to suddenly more pure and the same dose you took before can have more heroin in it …or it can be adulterated with fentanyl or other substances that can kill you
- environment and changing environment plays a role
- having undergone treatment, lost tolerance and then took same dose
- in one study of overdose patients:
85% of them had a depressant
45% of those depressants were benzodiazepines
36% had alcohol
most OD’s occur in combination with other drugs
What is naloxone? how does it prevent overdose?
naloxone is a fast acting opiod antagonist but only lasts 20-30 minutes
can reverse the opioid induced respiratory depression, coma and mitosis and prevent death if given within minurtes of the overdose
What is nalmefene? how does it prevent OD?
namefene is newer and longer lasting (4-8 hours)
they precipitate withdrawal symptoms if given to someone abusing opioids… so they will jump out of their coma all hyper and run away or do something violent
no significant effects on undrugged subjects so its pretty safe
what are the withdrawal symptoms of opioids?
can start to get symptoms four hours or less after previous use
start to feel ill six to eight hours after a dose
you need three to four injections per day to stop feeling ill
intensity and duration of symptoms are correlated with the intensity and duration of the drug’s effects
e.g. heroin is super intense and short effects so it has a super intense but short withdrawal
but methadone is mild but prolonged and never really gets to those far stages
what are some of the withdrawal symptoms associated with NorE release?
- chronic opioid use suppresses firing rate of adrenergic neurons in locus cereus (LC) which results in less norE release
- tolerance develops in the presence of chronic opiate exposure, firing rate and norE levels start to normalize
when opiates are removed, LC becomes hyperactive, and you get massive norE release and withdrawal symptoms
chills, sweating, stomach cramps, diarrhea, muscle pain, runny nose and eyes
What is clonidine and lofexidine and how does it prevent norE effects?
clonidine and lofexidine are non-opoiod alpha-2-adrenoreceptor agonists
bind to presynaptic alpha-2adrenergic autoreceptor to prevent release of NE from LC
do not address psychological issues like craving but can lead to low BP
used in detoxification process
does address many of the physical symptoms of withdrawal and can be used alongside methadone or buprenophine
What is methadone used for?
Used as maintenance treatment
methadone is a synthetic opioid used to substitute for the opioid that was being used
it has a long half life compared to heroin and never reaches the “high” or “extreme withdrawal” of heroin so it is not harmful
it is clean, pure and free to addicts
it has some mood elevating effects but euphoric effects are minimimal but it still causes constipation
taken orally
also NMDA Glutamate antagonist and shown to prevent mortality, HIV risk and crime
comes in a syrup
what is Buprenophrine
used as maintenance treatment
semi-synthetic partial agonist with higher affinity at mu receptors then morphine so it blocks effects of heroine but has mild effects
taken orally –> 37 hour half life so requires 1-3 doses per week as compared to methadone which is everyday dose and can be time consuming
does not cause respiratory depression
causes constipation in some
overall better safety profile than methadone because of the lower OD risk and lower recreational use and better tolerability
reported to be easier to withdraw form than methadone
what is agonist/antagonist therapy used for in maintenance?
combination of buprenophrine and naloxone (4:1 ratio)
If taken sublingually, naloxone has no effect and the partial agonist effects of buprenorphine are felt
if patient tries to inject, the naloxone will cause daily immediate withdrawal effects (so it is aversive for injection addicts…)
what is W-18?
attempt to synthesize non-addictive painkiller
originally thought to an opioid thats 100 Tims more potent than fentanyl
it does not bind to opioid receptors and naloxone will not reverse its effects
no one knows what it does
